The present invention relates to a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester, which is an ascorbic acid derivative useful as a cosmetic, a medical product or a food additive and widely used in various industrial fields including these.
In general, ascorbic acid (vitamin C) is known to have various physiological and pharmacological activities.
For example, ascorbic acid is used as a whitening cosmetic because of its effect of preventing melamine pigmentation, or as an artificial feed additive for preventing cultured fish from vitamin C deficiency. However, the ascorbic acid is unstable in oxygen or heat and readily undergoes coloration or degradation. Therefore, ascorbic acid generally used is stabilized against oxygen, heat or the like by forming the hydroxyl group at the 2-position of an ascorbic acid into a phosphoric ester. More specifically, ascorbic acid widely used is a vitamin C derivative easily soluble in water, in the form of a salt, particularly magnesium salt, of an ascorbic acid-2-phosphoric ester.
The process for producing an ascorbic acid-2-phosphoric ester magnesium salt (hereinafter sometimes referred to as xe2x80x9cAPMxe2x80x9d) from an ascorbic acid-2-phosphoric ester (hereinafter sometimes referred to as xe2x80x9c2-APxe2x80x9d) using magnesium oxide, magnesium hydroxide, magnesium carbonate or the like is described in a large number of publications and patents such as JP-B-52-18181 (the term xe2x80x9cJP-Bxe2x80x9d as used herein means an xe2x80x9cexamined Japanese patent publicationxe2x80x9d), JP-A-59-51293 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d) and JP-A-2-279690. However, specific conditions in the operation are not reported in detail.
JP-A-2-286693 describes a technique of adding magnesium oxide to an aqueous solution containing 2-AP obtained by phosphorylating 5,6-isopropylidene-L-ascorbic acid, while adjusting the pH using KOH to 8.5 to 9.0, separating the undissolved content by filtration, evaporation-concentrating the resulting solution, further crystallizing the solution with methanol, and filtering the solids obtained to produce APM.
However, in the case where APM is produced under the above-described conditions, excess phosphoric acid or a salt thereof is liable to intermingle in the product in a higher content or since the sedimentation of suspended matters is not completed within a short time, the filtration resistance increases and a washing operation is separately necessary. Thus, this technique is disadvantageous in the cumbersome process and also not satisfied in view of the cost.
In general, in the case of obtaining 2-AP by the phosphorylation reaction of an ascorbic acid, excess phosphoric acid, which is generated from the phosphorylating agent added and which cannot be completely removed in the purification step, remains in the solution obtained. This excess phosphoric acid reacts with a part of magnesium oxide added for the neutralization reaction of 2-AP and forms insoluble magnesium phosphate which is afterward separated by filtration and removed as an impurity. However, under conventional conditions, the magnesium phosphate cannot exhibit sufficiently high reactivity or precipitating property. Therefore, the excess phosphoric acid or magnesium phosphate intermingles in the solution of the step to adversely affect the product quality, and also a load is imposed on the filtering medium at the filtration of the residue, which is necessary in the next step.
The present invention has been made under these circumstances and provides a process for producing an ascorbic acid-2-phosphoric ester salt, where an ascorbic acid-2-phosphoric ester salt solution reduced in the content of excess phosphoric acid or a salt thereof mingled in the solution can be obtained from a solution containing an ascorbic acid-2-phosphoric ester or a salt thereof and a phosphoric acid or a salt thereof, with industrially high efficiency.
As a result of extensive investigations to solve the above-described problems, the present inventors have found that when an alkaline earth metal compound is added to a solution containing an ascorbic acid-2-phosphoric ester or a salt thereof and also containing phosphoric acid or a salt thereof, under a predetermined temperature condition to have a pH within a constant range, free phosphoric acid can be removed in the form of insoluble phosphoric acid alkaline earth metal having good precipitating property without imposing a load on the filtration medium. Thereby an ascorbic acid-2-phosphoric ester alkaline earth metal salt freed from any effect of the phosphoric acid contained on the quality can be produced efficiently.
More specifically, the present invention relates to the following embodiments:
(1) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester, comprising adding an alkaline earth metal compound to a stock solution containing an ascorbic acid-2-phosphoric ester or a salt and a phosphoric acid or a salt thereof, at a liquid temperature of 0 to 30xc2x0 C. to adjust the pH to 8.5 to 10.5;
(2) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in (1) above, which comprises a step of precipitating and separating the alkaline earth metal salt of phosphoric acid and recovering the supernatant;
(3) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in (2) above, which comprises precipitating and separating the alkaline earth metal salt of phosphoric acid and concentrating and crystallizing the supernatant recovered to obtain an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester;
(4) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in any one of (1) to (3) above, wherein the molar ratio of the phosphoric acid or a salt thereof to the ascorbic acid-2-phosphoric ester or a salt thereof in the stock solution is from 0.02 to 0.5;
(5) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in any one of (1) to (4) above, wherein after the step of precipitating and separating the alkaline earth metal salt of phosphoric acid and recovering the supernatant, the molar ratio of the phosphoric acid or a salt thereof to the alkaline earth metal salt of an ascorbic acid-2-phosphoric ester in the supernatant is less than 0.02;
(6) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in any one of (1) to (5) above, wherein the alkaline earth metal is magnesium;
(7) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in any one of (1) to (6) above, wherein the alkaline earth metal compound is an oxide or hydroxide of an alkaline earth metal;
(8) a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester as described in any one of (1) to (7) above, wherein the stock solution has a pH of 3 or less.
The present invention is described in detail below.
The present invention relates to a process for producing an alkaline earth metal salt of an ascorbic acid-2-phosphoric ester, comprising adding an alkaline earth metal compound to a stock solution containing an ascorbic acid-2-phosphoric ester or a salt and also containing a phosphoric acid or a salt thereof, at a liquid temperature of 0 to 30xc2x0 C. to adjust the pH to 8.5 to 10.5.
In the production process of an ascorbic acid-2-phosphoric ester alkaline earth metal salt of the present invention, the starting solution is not particularly limited as long as it is a solution containing 2-AP. Any of a 2-AP solution, a 2-AP alkali metal salt solution or a 2-AP alkaline earth metal salt solution may be used. For example, a 2-AP-containing solution obtained by directly phosphorylating ascorbic acid (see, JP-B-433-9219, JP-B-45-23746, JP-A-6-345786) and a 2-AP-containing solution obtained by phosphorylating 5,6-O-isopropylidene-L-ascorbic acid (see, JP-B-43-9219, JP-B-45-4497, JP-B-45-30328 and JP-B-59-4438) may be suitably used. In addition, a 2-AP-containing solution produced by the action of an enzyme or microorganism from an L-ascorbic acid and a phosphoric acid donor (see, JP-A-2-42996), and the like may also be used.
The 2-AP for use in the present invention is not particularly limited, and L-form 2-AP and DL-form 2-AP may be used. Among these, L-form 2-AP is preferred.
The stock solution used in the present invention means an aqueous solution containing phosphoric acid at a molar ratio PO4/2-AP in the range from 0.02 to 0.5. If the molar ratio PO4/2-AP is less than 0.02 or exceeds 0.5, the effect of the present invention is disadvantageously low.
In the case where the 2-AP is a salt or the 2-AP-containing solution contains an alkali metal or an alkaline earth metal, the solution is preferably decationized by treating it with an appropriate ion exchange resin. For the decationization, a general method may be used, such as a method where 2-AP is adsorbed to an ion exchange resin, eluted with from 0.1 to 2N dilute hydrochloric acid and then neutralized with an alkaline earth metal salt.
In the production process of the present invention, it is necessary to add an alkaline earth metal compound to a 2-AP solution at a liquid temperature of 0 to 30xc2x0 C. to adjust the pH of 8.5 to 10.5. The temperature range of the 2-AP solution is suitably from 0 to 30xc2x0 C., preferably from 5 to 25xc2x0 C., more preferably from 10 to 20xc2x0 C. If the liquid temperature is less than 0xc2x0 C., freezing may occur and this is not preferred, whereas if it exceeds 30xc2x0 C., the separability of insoluble impurities is disadvantageously deteriorated.
At the time when the addition of an alkaline earth metal compound is started, the pH is suitably 3 or less, preferably from 0.5 to 2. After the addition of the alkaline earth metal compound, the pH is suitably from 8.5 to 10.5, preferably from 9.0 to 10.5, more preferably from 9.0 to 10.0. If the pH after the addition of the alkaline earth metal compound is less than 8.5, the yield of APM disadvantageously decreases, whereas if it exceeds 10.5, the amount of unreacted alkaline earth metal compound increases and this is not preferred.
Even when the liquid temperature of the 2-AP solution is within the range from 0 to 30xc2x0 C., if the pH deviates from the above-described range, for example, if the pH after the addition of the alkaline earth metal compound is less than 8.5, the phosphoric acid cannot be satisfactorily removed and this is not preferred. Furthermore, the precipitating property of insoluble matters disadvantageously decreases in the case where the 2-AP solution contains a large amount of phosphoric acid, which is an impurity if the liquid temperature deviates from the above-described range, for example, if the liquid temperature exceeds 30xc2x0 C., even with a pH of 8.5 to 10.5.
Among the alkaline earth metal salts used in the present invention, a magnesium salt is preferred. Examples of magnesium include magnesium oxide, magnesium hydroxide and magnesium carbonate. Of these, magnesium oxide and magnesium hydroxide are preferred. In the present invention, when magnesium oxide is used for the neutralization reaction by an alkaline earth metal salt, the molar ratio of free phosphoric acid present in the solution during the step after the neutralization to APM becomes less than 0.02. Thereafter, undissolved matters are separated by filtration and the supernatant is recovered. This solution is concentrated and subsequently crystallized in an organic solvent, such as methanol, and the solids obtained are filtered. Then, APM is obtained.
In the present invention, after the undissolved matters as impurities are separated by filtration and the recovered supernatant is concentrated, the solution is crystallized by a conventionally known method to obtain the objective alkaline earth metal salt of 2-AP and the salt obtained is further dried and pulverized, whereby powdered 2-AP alkaline earth metal salt can be obtained.
As such, in the present invention, at the time of performing a neutralization reaction of the 2-AP salt by adding an alkaline earth metal compound, the solution temperature is controlled to a range from 0 to 30xc2x0 C. and also the pH of 3 or less is adjusted to a range from 8.5 to 10.5, whereby an alkaline earth metal salt of 2-AP can be efficiently produced.